Dr Sondak on Distinguishing Between Basal Cell Carcinoma and Cutaneous Squamous Cell Carcinoma

“Squamous cell cancer is characterized by [significant] ultraviolet [UV]-induced mutations from the heavy sun exposure that causes most cases of squamous cell cancer. This makes it susceptible to immunotherapy. Basal cell cancers also have a UV origin, a UV etiology, but they’re sometimes more associated with heavy, intermittent sun exposure, rather than really continuous, chronic sun exposure. So squamous cell cancers tend to respond better to immunotherapy than basal cell [cancers].”

Vernon Sondak, MD, the Richard M. Schulze Family Foundation Distinguished Endowed Chair in Cutaneous Oncology and chair of the Department of Cutaneous Oncology at Moffitt Cancer Center, and a professor in the Departments of Oncologic Sciences and Surgery at the University of South Florida Morsani College of Medicine, discussed the importance of accurately distinguishing advanced cutaneous squamous cell carcinoma (CSCC) from basal cell carcinoma (BCC).

In the advanced setting, the risk of recurrence and metastasis is generally higher with CSCC than with BCC, even though both carry a lower metastatic potential compared with more aggressive skin cancers such as melanoma or Merkel cell carcinoma, Sondak said. This distinction becomes especially relevant as systemic therapy considerations come into play, given that treatment strategies diverge based on tumor subtype.

BCC is largely characterized by alterations in the hedgehog signaling pathway, rendering these tumors uniquely susceptible to hedgehog pathway inhibitors, Sondak stated. These agents, however, do not demonstrate activity in CSCC, melanoma, or other cutaneous malignancies. In contrast, CSCC typically harbors a high tumor mutational burden driven by chronic UV exposure. This ultraviolet (UV)–induced mutational landscape enhances tumor immunogenicity and underpins the clinical activity of immune checkpoint inhibitors in this disease, Sondak underscored. Although BCC also arises from UV damage, CSCC tends to demonstrate more robust and consistent responses to immunotherapy.

Given these biologic differences, confirming the correct histologic diagnosis is essential, Sondak emphasized. Although most cases can be accurately classified based on biopsy and routine pathologic evaluation, a small subset of tumors present with ambiguous features, demonstrating both basal and squamous differentiation, Sondak noted. In such scenarios, therapeutic decisions become more complex. Clinically, treatment responses may clarify the dominant biology; for example, hedgehog inhibition may suppress a basal component while allowing a squamous element to progress, whereas immunotherapy may preferentially control the squamous component.

To resolve diagnostic uncertainty, molecular profiling and next-generation sequencing can provide critical insight, Sondak added. Identification of a hedgehog pathway mutation strongly supports a diagnosis of BCC, whereas the presence of a high burden of UV-signature mutations without hedgehog alterations favors CSCC. Although traditional histopathology remains sufficient in approximately 95% to 98% of cases, advanced molecular workup plays an increasingly important role in select advanced or ambiguous presentations, Sondak concluded.